Different PfEMP1-expressing Plasmodium falciparum variants induce divergent endothelial transcriptional responses during cytoadherence
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ABSTRACT:
PROVIDER: PRJEB60450 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR10969707_1.fastq.gz | Fastqsanger.gz | |||
| ERR10969707_2.fastq.gz | Fastqsanger.gz | |||
| ERR10969708_1.fastq.gz | Fastqsanger.gz | |||
| ERR10969708_2.fastq.gz | Fastqsanger.gz | |||
| ERR10969709_1.fastq.gz | Fastqsanger.gz |
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Project description:The pathogenesis of severe malaria is complex and involves several pathways that influence host inflammation and endothelial function. The human malaria parasite Plasmodium falciparum is responsible for the majority of mortality and morbidity caused by malaria infection and differs from other human malaria species in the degree of accumulation of parasite-infected red blood cells in the microvasculature, known as cytoadherence or sequestration. In P. falciparum, cytoadherence is mediated by a protein called PfEMP1 which, due to its exposure to the host immune system, undergoes antigenic variation resulting in the expression of different PfEMP1 variants on the infected erythrocyte membrane. These PfEMP1s contain various combinations of adhesive domains, which allow for the differential engagement of a repertoire of endothelial receptors on the host microvasculature, with specific receptor usage associated with severe disease. Cytoadherence results in perturbation of the micro-circulation as well as direct effects on endothelial cells promoted by receptor-mediated signalling. We used a co-culture model of cytoadherence incubating human brain microvascular endothelial cells with erythrocytes infected with two parasite lines expressing different PfEMP1s; IT4var14 (long-form; ups B) that binds strongly to human brain microvascular endothelial cells mainly via ICAM-1, and IT4var 37 (short-form; ups C) that does not bind brain endothelium but shows high levels of binding to human dermal microvascular endothelial cells via CD36. We determined the transcriptional profile of the endothelial cells following different incubation periods with infected erythrocytes, identifying different transcriptional profiles of pathways involved in the pathology of severe malaria, such as inflammation, apoptosis and barrier integrity, induced by the two PfEMP1 variants.
2023-11-01 | E-MTAB-12730 | biostudies-arrayexpress
Project description:The variant antigen, Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), expressed on the surface of P. falciparum infected Red Blood Cells (iRBCs) is a critical virulence factor for malaria. Each parasite encodes 60 antigenically distinct var genes encoding PfEMP1s, but during infection the clonal parasite population expresses only one gene at a time before switching to the expression of a new variant antigen as an immune evasion mechanism to avoid the hostM-bM-^@M-^Ys antibody responses. The mechanism by which 59 of the 60 var genes are silenced remains largely unknown. We used microarrays to detail the global programme changes of gene expression caused by each gene knockout with a particular view towards which gene knockout results in transcriptional upregulation of the entire var gene family. Plasmodium falciparum clones, in each of which one of different histone lysine methylation modification enzyme genes was knocked out, were synchronized in the asexual stage and collected at indicated time points post invasion of erythrocytes for RNA extraction and hybridization on Affymetrix microarrays. We sought to identify the key epigenetic enzyme that controls silencing of the whole var gene family.
2013-05-25 | E-GEOD-47349 | biostudies-arrayexpress
Project description:Epigenetic processes are the main conductors of phenotypic variation in eukaryotes. The malaria parasite Plasmodium falciparum employs antigenic variation of the major surface antigen PfEMP1, encoded by 60 var genes, to evade acquired immune responses. PfEMP1 also mediates sequestration of infected erythrocytes in the microvasculature, which is directly linked to severe malaria outcomes. Antigenic variation of PfEMP1 occurs through in situ switches in mono-allelic var gene transcription, which is PfSIR2-dependent and associated with the presence of repressive H3K9me3 marks at silenced loci. Here, we show that the P. falciparum ortholog of heterochromatin protein 1 (PfHP1) binds to H3K9me3 and constitutes a major component of heterochromatin in perinuclear chromosome end clusters. High-resolution genome-wide chromatin immuno-precipitation demonstrates the striking association of PfHP1 with non-syntenic virulence gene arrays in subtelomeric and chromosome-internal islands. These include not only var genes but the majority of P. falciparum lineage-specific gene families coding for exported proteins involved in host-parasite interactions. Over-expression of PfHP1 resulted in decreased expression of a small number of (virulance) genes and indicated the presence of well-defined heterochromatic boundaries.. In summary, we uncover an unprecedented function of HP1 as a mayor regulator of virulence gene silencing and phenotypic variation, which will be instrumental for our understanding of this widely used survival strategy of unicellular pathogens. one experimental sample
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Project description:Plasmodium falciparum variant antigens named erythrocyte membrane protein 1 (PfEMP1) are important targets for developing a protective immunity to malaria caused by P. falciparum. One of the major challenges in P. falciparum proteomics studies is identifying PfEMP1s at the protein level due to antigenic variation. To identify these PfEMP1s using shotgun proteomics, we developed a pipeline that searches high resolution mass spectrometry spectra against a custom protein sequence database. An algorithm, LAX, was developed as part of the pipeline that matches sequences to the most similar PfEMP1 and calculates a weight value used for PfEMP1 protein inference. The pipeline was first validated in the analysis of a laboratory strain with a known PfEMP1, then it was implemented on the analysis of parasite isolates from malaria-infected pregnant women and finally on the analysis of parasite isolates from malaria infected children where there was an increase of PfEMP1s identified in 28 out of 31 isolates.
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Project description:The variant antigen, Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), expressed on the surface of P. falciparum infected Red Blood Cells (iRBCs) is a critical virulence factor for malaria. Each parasite encodes 60 antigenically distinct var genes encoding PfEMP1s, but during infection the clonal parasite population expresses only one gene at a time before switching to the expression of a new variant antigen as an immune evasion mechanism to avoid the host’s antibody responses. The mechanism by which 59 of the 60 var genes are silenced remains largely unknown. We used microarrays to detail the global programme changes of gene expression caused by each gene knockout with a particular view towards which gene knockout results in transcriptional upregulation of the entire var gene family.
2013-05-25 | GSE47349 | GEO
Project description:The malaria parasite, Plasmodium falciparum, traffics the virulence protein P. falciparum erythrocyte membrane protein 1 (PfEMP1) to the surface of infected red blood cells (RBCs) via membranous organelles known as the Maurer’s clefts. We developed a method for efficient enrichment of Maurer’s clefts and profiled the protein composition of this trafficking organelle. We identified 18 previously uncharacterised or poorly characterised Maurer’s cleft proteins. Transfectants expressing GFP-fusions of 7 of these proteins and confirmed their Maurer’s cleft location. Co-immunoprecipitation and mass spectrometry identified interacting partners of these Maurer’s clefts proteins, providing a network map of protein-protein associations. We identified two key clusters of proteins that may function in the loading and unloading of PfEMP1 into and out of the Maurer’s clefts.
2020-02-20 | PXD014873 | Pride
Project description:Epigenetic processes are the main conductors of phenotypic variation in eukaryotes. The malaria parasite Plasmodium falciparum employs antigenic variation of the major surface antigen PfEMP1, encoded by 60 var genes, to evade acquired immune responses. PfEMP1 also mediates sequestration of infected erythrocytes in the microvasculature, which is directly linked to severe malaria outcomes. Antigenic variation of PfEMP1 occurs through in situ switches in mono-allelic var gene transcription, which is PfSIR2-dependent and associated with the presence of repressive H3K9me3 marks at silenced loci. Here, we show that the P. falciparum ortholog of heterochromatin protein 1 (PfHP1) binds to H3K9me3 and constitutes a major component of heterochromatin in perinuclear chromosome end clusters. High-resolution genome-wide chromatin immuno-precipitation demonstrates the striking association of PfHP1 with non-syntenic virulence gene arrays in subtelomeric and chromosome-internal islands. These include not only var genes but the majority of P. falciparum lineage-specific gene families coding for exported proteins involved in host-parasite interactions. Over-expression of PfHP1 resulted in decreased expression of a small number of (virulance) genes and indicated the presence of well-defined heterochromatic boundaries.. In summary, we uncover an unprecedented function of HP1 as a mayor regulator of virulence gene silencing and phenotypic variation, which will be instrumental for our understanding of this widely used survival strategy of unicellular pathogens.
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Project description:PfEMP1 is a variable antigen displayed on red blood cells (RBCs) infected with the malaria parasite Plasmodium falciparum. PfEMP1 mediates binding of the infected cell to the endothelium of blood vessels, a major cause of severe manifestations of malaria. Each parasite encodes ∼60 different PfEMP1 variants of which only one is expressed at a time and switching between variants underlies immune evasion in the host and variant-specific severity of disease. PfEMP1 expression heterogeneity between parasites complicates its study and hampers genetic modification approaches as in many cells the modified locus is not expressed. Here we used selection linked integration to generate parasites all expressing the same PfEMP1 variant and permitting genomic modification of the expressed locus. Using this system, we study PfEMP1 trafficking, generate cell lines binding to all major endothelial receptors, survey the protein environment from functional PfEMP1 in the host cell and identify new proteins needed for PfEMP1 mediated sequestration. Overall, these approaches facilitate the study of the molecular and cellular biology of the key virulence factor of malaria parasites.
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